Type 2 conventional dendritic cells play a critical role in the disease outcome of Leishmania mexicana infection, but not in Leishmania major infection

Depending on the parasite species, cutaneous leishmaniasis (CL) in C57BL/6 mice differs in the disease outcome. Leishmania (L). major infection usually shows a strong Th1-driven interferon (IFN)γ response and subsequent production of leishmanicidal nitric oxide, limiting parasite growth and skin pathology, whereas L. mexicana infection ends up in chronic skin lesions due to a mixed IFNγ and interleukin (IL)-10 Th response. As Th responses are triggered by myeloid antigen-presenting cells, we hypothesized that differences in the infection and/or functionality of myeloid subpopulations at the site of infection control disease progression in self-healing versus chronic CL.

Using fluorescently labeled Leishmania and flow cytometry, we identified dendritic cells (DCs), monocytes, macrophages and granulocytes as Leishmania host cells in the skin early after infection. Dermal cDC2 showed higher infection rates than cDC1 in both infections. Single-cell RNA sequencing during early L. major and L. mexicana infection revealed that there is a distinct Cxcl9-positive macrophage population present in the draining lymph nodes of L. mexicana-infected mice, but not of L. major-infected animals after 24 hrs of infection. Other myeloid cell subclusters in skin and lymph nodes after 24 and 120 hrs of infection were similar for both parasites. To study the role of cDC2s in vivo, we analyzed Irf4ΔItgax mice that have reduced levels of cDC2 in their lymphoid organs. L. major-infected cDC2-deficient mice and wild-type (WT) littermates showed a comparable, self-healing course of disease. In contrast, L. mexicana infection caused the expected chronic skin lesions in WT controls, whereas L. mexicana-infected Irf4ΔItgax mice developed only mild pathology and resolved the disease. Quantitative PCR analysis of the infected tissue of these animals revealed a shift towards a stronger Th1 response and a subsequent dampening of Th2 related gene expression. Thus, cDC2 exert a hitherto unknown detrimental effect in chronic CL. Ongoing studies aim to unravel the disease-promoting mechanism of cDC2.